Multidrug resistance (MDR) is a limiting factor to clinical outcome of chemotherapy. One such resistance mechanism is that mediated by the overexpression of drug efflux transporters such as permeability-glycoprotein (P-gp) and Multidrug resistance protein 1 (MRP1), also called ABCC1 and other proteins in the ABCG2 family. These protein transporters drive out diverse anticancer agents, resulting in lowered intracellular concentration of drug. Unlike P-glycoprotein, MRP1 pumps hydrophilic drugs either conjugated (e.g. glucuronate, sulfate) or unconjugated. The discovery of chemosensitizing or modulating agents against P-gp has attracted interest from both academia and industry. The calcium channel blocker Verapamil was one of the first compounds reported to reverse resistance by inhibiting P-gp-mediated drug efflux (Tsuruo et al., Cancer Res 1981, 41, 1967-1972). Since then, there is a considerable body of data suggesting that MDR due to P-gp can be effectively modulated by a range of compounds including dexverapamil, dexniguldipine, PSC 833 (Twentyman, P. R. et al. Eur J Cancer 1991, 27, 1639-1642) and VX-710. These second generation MDR modulators have shown encouraging results, but their clinical utility is limited by reportedly unpredictable drug-drug interaction (Lum, B. L et al. Hematol Oncol Clin North Am 1995, 9, 319-336). Third generation MDR modulators including zosuquidar LY335979, tariquidar XR9576, laniquidar R101933, the acridonecarboxamide GF120918 and the substituted diarylimidazole ONT-090 have been developed in effort to overcome the limitations of second generation compounds.
Flavonoids represent a promising class of compounds for modulating MDR, in part because they have generally low toxicity. Chrysin, quercetin, kaempferol and dehydrosilybin are reported to bind to the NBD2 cytosolic domain of mouse P-gp (Di Pietro A. et al. Cell. Mol. Life. Sci. 2002, 59, 307-322.). Even with their low toxicity, known flavonoids have only moderate activity as modulators of MDR. They have a broad spectrum of biological activity including anti-estrogen activity and they inhibit other ATPases. High doses of flavonoids as MDR modulators may cause side effects. Flavonoid dimers that sensitize chemorestistant tumors or parasitic infection including Leishmania have been characterized. (Chan, K. F. et al. J Med Chem 2006, 49, 6742-6759; Chan, K. F. et al. Chem. Med. Chem. 2009, 4, 594-614; Wong, I. L. et al. Antimicrob Agents Chemother 2007, 51, 930-940; Wong, I. L. et al. J Med Chem 2009, 52, 5311-5322; Wong, I. L. et al. Leishmania. J Antimicrob Chemother 2009, 63, 1179-1190; WO 2007/135592). The compounds inhibit membrane transporters like P-gp and MRP1 which would otherwise cause drug efflux. On the other hand, there is a limitation to the potential use of these flavonoid dimers in a clinical setting. Their modulating activity is not as potent compared to other compounds previously. More importantly, these compounds are quite insoluble in water or in non-polar organic solvents such as octanol and may not be well absorbed in vivo.
Leishmaniasis is one of several major parasitic diseases targeted by the World Health Organization (WHO). Leishmaniasis is endemic in over eighty countries in the world. More than 350 million people are at risk of infection and about two million people are infected annually. 500,000 of these cases are of the visceral form which could be fatal if left untreated. Currently, there is no vaccine for leishmaniasis. One treatment regimen is chemotherapy including pentavalent antimonials (SbV) which has been used for more than 50 years. Antimonials are not ideal due to the difficulty of administration, side effects and emergence of antimonials-resistant cases. It has been reported that more than 50% of the visceral leishmaniasis cases in India are resistant to the antimonials (Shyam S. et al. Am. J. Trop. Med. Hyg, 1997, 56, 522-5).
Leishmaniasis is responsible for considerable morbidity and mortality worldwide. However, chemotherapy currently available for treating leishmaniasis is far from satisfactory because of limited efficacy, toxic side effects, need for prolonged hospitalization during treatment period and emergence of drug resistance. There is an urgent need for novel, safer and more efficacious antileishmanial medicaments. Newer antileishmanials such as amphotericin B, miltefosine and paromomycin also have intrinsic limitations including toxicity, low efficacy, cost and inconvenient treatment protocol.
Plant derived compounds have recently been reported to exhibit antiparasitic properties of surprising efficacy and selectivity (Kayser, O. et al. Parasitol Res 2003, 90 Suppl 2, S55-62.). Flavonoids have been reported to have a wide range of biological activity, particularly as antioxidative and anticancer agents. Flavonoids represent a large family of polyphenolic compounds found in vegetables and fruits. Because humans consume large quantities of flavonoids in the diet, it is generally accepted that flavonoids are safe. The general structure of flavonoids contains a flavin nucleus with two aromatic rings (A and B rings) interconnected by third heterocyclic ring C. The most common flavonoids are flavone and isoflavone (Tasdemir, D.; et al. Antimicrob Agents Chemother 2006, 50, 1352-1364).
Biflavonoids are characterized by two flavonoid monomeric units (flavone or flavanone) covalently linked either with C—C or C—O—C bonds. Biflavonoids are rich in many species of plant and reported to have significant antiviral and antiprotozal activity (Weniger, B. et al. Phytomedicine 2006, 13, 176-180). Weniger et al. has reported that lanaroflavone, bilobetin, ginkgetin, isoginkgetin and sciadopitysin exhibit anti-axenic amastigote activity in vitro.
The mode of action of flavonoids has been investigated. For the, proanthcyanidins, the leishmanicidal activity was reported to be due to macrophage activation rather than direct antiparasitic activity by generation of nitric oxide and tumor necrosis factor-α (Kolodziej, H. et al. Biol Pharm Bull 2001, 24, 1016-1021). Quercetin and luteolin inhibit topoisomerase and induce cell cycle arrest leading to apoptosis of Leishmania (Mitta, B.; et al. Mol Med 2000, 6, 527-541). A biflavonoid, 2″, 3″-diidroochnaflavone, isolated from the leaves of Luxemburgia nobilis, has been reported as cytotoxic to murine Ehrlich carcinoma and human leukemia K562 cells and found to have inhibitory activity of topoisomerase I and II-α(Oliveira, M. C. et al. Planta Med 2005, 71, 561-563). Morelloflavone, a biflavonoid, was found to inhibit tumor angiogenesis by targeting Rho GTPase and extracellular signal-regulated kinase signaling pathway (Pang, X. et al. Cancer Res 2009, 69, 518-525).
There is a need to provide compounds that are able to overcome at least one, but preferably more, of the problems as set forth in the prior art. It would be desirable to have effective against promastigotes and amastigotes. It would further be desirable to have compounds that are safe and non toxic to macrophages, and easy to synthesize.